Metabolic and Endocrine Effects of Bariatric Surgery

描述(申请人提供)：减肥手术通常是治疗肥胖症最有效的方法。Roux-en-Y胃分流术(RYGB)也可能是治疗2型糖尿病(DM)最有效的方法之一。腹腔镜胃捆绑(LAGB)是另一种减肥方法，可减轻体重并改善血糖控制。在LAGB中，T2 DM患者恢复正常血糖主要是由于体重减轻的程度。相反，我们已经证明RYGB与肠道激素分泌的变化有关，这可能会促进食欲下降、饱腹感增加、胰岛素敏感性和分泌。最近，另一种减肥手术，袖状胃切除术(SG)，作为一种单一的手术方式得到了青睐，而在此之前，它是吸收不良手术之前的第一阶段。对SG的了解要少得多，但一些数据表明，体重减轻和代谢结果，包括肠道激素的变化，与RYGB惊人地相似。因此，与LAGB和饮食热量限制相比，神经激素机制可能有助于RYGB和SG后更大的体重减轻和血糖控制的改善。这项提案的主要目标是进一步描述不同减肥方式后发生的代谢和内分泌变化。在AIM One中，将接受极低热量饮食的DM患者与接受RYGB和SG的患者进行比较，以确定手术对胰岛素敏感性和分泌的特异性影响。受试者也将在一年内接受跟踪。在实验二中，通过分级输注葡萄糖和精氨酸刺激来检测RYGB或SG前后的胰岛细胞最大功能和胰升糖素抑制情况，并与瘦体对照组进行比较。本研究的目的是确定是否有证据表明RYGB后的胰岛细胞增殖可能是由于长期暴露于浓度增加的胰高血糖素样肽1所致。AIM 3的主要目标是继续表征LAGB和RYGB后的胃肠激素和载脂蛋白A-IV的分泌，以及与体重减轻和食欲的关系以及前瞻性的长期随访。我们还将在SG之后开始刻画角色。我们将与索纳博士合作，使用一种特殊的双部位夹心试验来分析这些程序对酰基和去酰基生长激素释放素的影响。AIM Four的目标是与Burant博士和密歇根大学代谢组学核心中心合作，使用液、气相色谱和质谱仪研究DM患者和非DM患者VLCD、LAGB、RYGB和SG治疗前后~200种代谢物的变化，包括氨基酸、脂质种类和葡萄糖中间体。最终目标是了解不同减肥方式后促进减肥/维持体重和血糖动态平衡的机制。这些信息将帮助患者和医生选择适当的治疗方法，并指导开发更有效的非手术治疗肥胖症和糖尿病。 与公共卫生相关：伴随着病态肥胖率的指数增长，2型糖尿病患者的人数增加，接受减肥手术治疗这些威胁生命的慢性疾病的人数也增加。这些研究的目的是了解促进减肥、改善血糖控制和/或缓解糖尿病的机制。最终目标不仅是确定肥胖和糖尿病的非手术治疗途径，而且还确定与手术结果相关的临床变量，这些变量将使考虑减肥手术同时治疗肥胖症和糖尿病的个人的风险：收益比最大化。

DESCRIPTION (provided by applicant): Weight loss surgery is usually the most effective treatment of obesity. Roux-en-Y gastric bypass (RYGB) surgery may also be one of the most effective treatments for type 2 diabetes (DM). Laparoscopic gastric banding (LAGB) is another weight loss procedure that results in a lesser degree of weight loss and improvement in glycemic control. In LAGB, the return to euglycemia in T2DM patients is predominantly due to the magnitude of weight loss. In contrast, we have shown that RYGB is associated with changes in gut hormone secretion that may promote decreased appetite, increased satiety, insulin sensitivity and secretion. More recently another bariatric procedure, sleeve gastrectomy (SG), has come into favor as a single procedure, when prior it was the first stage preceding malabsorptive operations. Much less is known about SG, but some data suggest that weight loss and metabolic outcomes, including gut hormone changes, are surprisingly similar to RYGB. Thus, it is likely that neurohormonal mechanisms contribute to greater weight loss and improvement in glucose control after RYGB and SG compared with LAGB and dietary caloric restriction. The main objectives of this proposal are to further delineate the metabolic and endocrine changes that occur after different weight loss modalities. In AIM ONE subjects with DM placed on an in-patient very low calorie diet will be compared with individuals undergoing RYGB and SG before and after equivalent weight loss (7- 10% of body weight) achieved over the same time period (3 wks) in order to determine surgery specific effects on insulin sensitivity and secretion. Subjects will also be followed at 1 year. In AIM TWO, glucagon suppression and maximal islet cell function will be measured by a graded glucose infusion and arginine stimulation before and after RYGB or SG and compared with lean controls. The purpose of this study is to determine if there is evidence of islet cell hyperplasia after RYGB that may occur as a result of chronic exposure to increased concentrations of glucagon-like peptide 1. The main objectives of AIM THREE are to continue characterization of gut hormone and apolipoprotien A-IV secretion after LAGB and RYGB and the relationship to weight loss and appetitive sensations with prospective long-term follow-up. We will also begin characterization after SG. The effect of these procedures on acyl- and des-acyl ghrelin using a specific two-site sandwich assay will be analyzed in collaboration with Dr. Thorner. The objective of AIM FOUR is to investigate alterations in ~200 metabolites, including amino acids, lipid species and glucose intermediates before and after VLCD, LAGB, RYGB, and SG in subjects with and without DM using liquid and gas chromatography and mass spectrometry in collaboration with Dr. Burant and the U of Michigan Metabolomics Core. The ultimate goal is to understand the mechanisms that promote weight loss/maintenance and glucose homeostasis after different weight loss modalities. This information would aid both the patient and physician in the selection of appropriate therapy and guide the development of more effective non-surgical treatments for obesity and DM. PUBLIC HEALTH RELEVANCE: Together with an exponential increase in morbid obesity is an increase in individuals with type 2 diabetes mellitus and an increase in individuals undergoing bariatric surgery to treat these chronic life-threatening conditions. The objective of these studies is to gain an understanding of mechanisms that promote weight loss, improved glucose control and/or remission of diabetes. The ultimate goal is not only to identify non- surgical therapeutic pathways for obesity and diabetes but also to identify clinical variables that are associated with surgical outcomes that will maximize the risk: benefit ratio for individuals considering bariatric surgery as a treatment for both obesity and diabetes.